Original ArticleCardiac DPD-uptake time dependency in ATTR patients verified by quantitative SPECT/CT and semiquantitative planar parameters
Introduction
Amyloidosis is a group of rare diseases originated by deposition of misfolded proteins leading to progressive multiorgan failure and death.1 The different types of amyloidosis include light-chain amyloidosis (AL), amyloid amyloidosis (AA), wild-type transthyretin amyloidosis (wtATTR) and the hereditary transthyretin amyloidosis (hATTR).2 ATTR is caused by instability of the tetramere transthyretin, a transport protein of thyroxine and retinol A with consecutive formation of misfolded aggregates from monomeres as insoluble amyloid fibrils with deposit in various organs. Typically, the heart, kidneys, peripheral nervous system and liver are affected. Whereas hATTR is related to mutations leading to destabilization of the TTR protein, wtATTR has an inherent, albeit low potential to form amyloid fibrils.3,4
Imaging studies have shown that radiolabeled phosphonates, such as [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), have a strong affinity for TTR amyloid fibrils in the heart. The exact mechanism of binding is not fully understood, but a high density of microcalcifications of ATTR seems to play an important role.5,6
Recently, several drugs have been developed for ATTR which have shown to reduce mortality in patients with known cardiac ATTR (cATTR).7,8 Therefore, the repetitive quantification of amyloid burden using imaging modalities for treatment monitoring has become increasingly important. Several studies have demonstrated the feasibility of standard uptake values (SUV) quantification of amyloid deposition on bone scintigraphy using SPECT/CT.9, 10, 11, 12, 13, 14, 15 However, quantification of cardiac amyloid deposition is subject to several drawbacks. There is a competition for the tracer uptake in the different compartments such as heart, soft tissue and bone.15 To correct for this influence on the SUV quantification, Scully and co-workers have developed a SUV retention index as recently described.12 In addition, cardiac tracer uptake does not appear to be constant over time.16,17 Therefore, the aim of this study was to track the time course of myocardial DPD tracer accumulation in patients with ATTR amyloidosis using planar and quantitative SPECT/CT imaging for better understanding of the tracer behavior and establishing a potential imaging protocol for therapy assessment.
Section snippets
Study population
Thirty-eight consecutive patients with verified ATTR amyloidosis [10 women and 28 men; age 79 ± 8 years, 33 patients wtATTR, 5 patients with hATTR (1 × Val50Met, 4 × His108Arg)] were considered for this study on the basis of the scintigraphic imaging protocols performed for cardiac amyloidosis evaluation.
Heart failure stage NYHA 1 was known in 4 patients, stage NYHA 2 in 13 patients and stage NYHA3 in 1 of the 38 patients. Heart failure with preserved ejection fraction (HFpEF) was observed in
Results
Based on the imaging procedures 23 patients (7 women, 16 men; age 78 ± 8 years) received planar 2-phase whole-body DPD-bone imaging 1.0 ± 0.4 and 2.9 ± 0.4 hours p.i.. Further 15 patients (3 women, 12 men; age 79 ± 8 years) underwent quantitative 2-phase SPECT/CT 1 hours p.i. (1.0 ± 0.2 hours) and 3 hours p.i. (2.9 ± 0.3).
Discussion
Bone scintigraphy has been recently accepted as an imaging tool together with the so called Perugini scoring system for the diagnosis of cATTR.23 With the development and introduction of several drugs reducing mortality in patients with cATTR bone scintigraphy may also become an important role in treatment monitoring in the future. Therefore, well-defined and understood quantification methods for this functional imaging are recommended beside a fixed time-point of imaging.
According to the
Study limitations
This study suffers from some limitations. Due to the time-consuming imaging procedures in a first-of-all clinical routine setting the number of patients investigated is explained. Nevertheless, almost exclusively patients with strong cardiac tracer uptake were included in the study, as we wanted to investigate the time dependence of the uptake behavior in patients with confirmed cATTR amyloidosis under the aspect of possible therapeutic intervention. Moreover, the low-dose CT component was only
New knowledge gained
DPD cardiac uptake is time-dependent as demonstrated by SPECT/CT based SUV quantification. Explained by an increased blood pool activity, but also by a possible stronger binding behavior of DPD to the amyloid deposit at an earlier time point, this observation should be considered for imaging guided therapy monitoring.
Conclusion
The results of this study revealed that DPD bone imaging in patients with cATTR for grading of the disease burden is affected by time-dependent cardiac, bone and soft-tissue tracer uptake kinetics using different imaging based analysis tools in a well-defined study cohort. Beside visual Perugini score changes in ~ 38% of cATTR patients also quantitative parameter are influenced. The observed significantly higher myocardial SUVpeak and the SUV retention index 1 hours p.i. compared to 3 hours
Funding
Open access funding provided by Medical University of Vienna.
Disclosure
Diana Bonderman received research grants and honoraria from Pfizer, Alnylam, SOBI and Ionis. Franz Duca received research grants from Pfizer and the Austrian society of cardiology and payment for lectures from Pfizer and Bayer as well as payment for expert testimony from Pfizer and Alnylam. He also received travel support from Pfizer, Novartis, Bayer, AOP and Alnylam. Rene Rettl received speaker fees and congress support from Akcea, Alnylam and Pfizer, as well as well as research grants from
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